Phenotypic plasticity of fibroblasts during mammary carcinoma development

  • Cancer-associated fibroblasts (CAFs) in the tumor microenvironment contribute to all stages of tumorigenesis and are usually considered to be tumor-promoting cells. CAFs show a remarkable degree of heterogeneity, which is attributed to developmental origin or to local environmental niches, resulting in distinct CAF subsets within individual tumors. While CAF heterogeneity is frequently investigated in late-stage tumors, data on longitudinal CAF development in tumors are lacking. To this end, we used the transgenic polyoma middle T oncogene-induced mouse mammary carcinoma model and performed whole transcriptome analysis in FACS-sorted fibroblasts from early- and late-stage tumors. We observed a shift in fibroblast populations over time towards a subset previously shown to negatively correlate with patient survival, which was confirmed by multispectral immunofluorescence analysis. Moreover, we identified a transcriptomic signature distinguishing CAFs from early- and late-stage tumors. Importantly, the signature of early-stage CAFs correlated well with tumor stage and survival in human mammary carcinoma patients. A random forest analysis suggested predictive value of the complete set of differentially expressed genes between early- and late-stage CAFs on bulk tumor patient samples, supporting the clinical relevance of our findings. In conclusion, our data show transcriptome alterations in CAFs during tumorigenesis in the mammary gland, which suggest that CAFs are educated by the tumor over time to promote tumor development. Moreover, we show that murine CAF gene signatures can harbor predictive value for human cancer.

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Author:Eiman Elwakeel, Mirko Brüggemann, Annika F. Fink, Marcel Holger SchulzORCiDGND, Tobias Schmid, Rajkumar SavaiORCiDGND, Bernhard BrüneORCiD, Katharina ZarnackORCiDGND, Andreas WeigertORCiDGND
Pubmed Id:
Parent Title (English):International journal of molecular sciences
Publisher:Molecular Diversity Preservation International
Place of publication:Basel
Document Type:Article
Year of Completion:2019
Date of first Publication:2019/09/09
Publishing Institution:Universitätsbibliothek Johann Christian Senckenberg
Release Date:2019/12/18
Tag:cancer; cancer-associated fibroblasts; gene signature; mammary carcinoma; transcriptional profiling
Issue:18, Art. 4438
Page Number:23
First Page:1
Last Page:23
This is an open access article distributed under the Creative Commons Attribution License which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited
Institutes:Medizin / Medizin
Biowissenschaften / Institut für Ökologie, Evolution und Diversität
Exzellenzcluster / Exzellenzcluster Makromolekulare Komplexe
Wissenschaftliche Zentren und koordinierte Programme / Sonderforschungsbereiche / Forschungskollegs
Dewey Decimal Classification:6 Technik, Medizin, angewandte Wissenschaften / 61 Medizin und Gesundheit / 610 Medizin und Gesundheit
Licence (German):License LogoCreative Commons - Namensnennung 4.0